The CB1 neutral antagonist AM4113 blocked fentanyl discrimination in rats at lower doses and without the response-suppressing side effects seen with rimonabant, supporting its potential as a novel opioid use disorder treatment.
Addiction pharmacologists, opioid use disorder researchers, and drug development scientists.
AM4113 blocked fentanyl effects at 10x lower doses than those affecting food intake
What the researchers found
AM4113 (0.32-1.0 mg/kg) effectively blocked fentanyl discrimination at doses that did not reduce food-maintained responding. Rimonabant (1.0-10 mg/kg) only partially attenuated fentanyl effects at the highest dose, which also significantly decreased response rates. Mu-opioid agonists fully substituted for fentanyl, confirming opioid mediation.
Why it matters
Current opioid use disorder treatments are limited. A CB1 neutral antagonist that blocks fentanyl effects without the psychiatric side effects that ended rimonabant could offer a new therapeutic approach.
The numbers in context
AM4113 effective doses: 0.32-1.0 mg/kg. Rimonabant partial effect only at 10 mg/kg (with rate suppression). AM4113 was effective at 10-fold lower doses than those affecting food responding.
How the study worked
Male rats trained to discriminate 0.032 mg/kg fentanyl from saline under a fixed-ratio 10 schedule of food reinforcement. Tested effects of CB1 neutral antagonist AM4113 and inverse agonist rimonabant on fentanyl discrimination and food-maintained responding.
What this study cannot tell us
Animal study in rats. Drug discrimination assay measures subjective effects, not addiction-related behaviors. Only male rats tested. Translation to human opioid use disorder uncertain.
How to read the evidence
Well-designed animal pharmacology study with appropriate controls, but requires human translation.
When this study was published
Published in 2022.
The bigger picture
The functional interaction between cannabinoid and opioid systems opens a novel therapeutic avenue for the opioid crisis, particularly since CB1 neutral antagonists may avoid the depression and anxiety that doomed rimonabant.
Questions still open
- Would AM4113 also block the reinforcing properties of fentanyl in self-administration models? Could CB1 neutral antagonists be used alongside existing opioid treatments?
Common questions
Could cannabinoid drugs help treat opioid addiction?
What is a neutral antagonist?
Read the original research
Effects of the cannabinoid CB1-receptor neutral antagonist AM4113 and antagonist/inverse agonist rimonabant on fentanyl discrimination in male rats.
Drug and alcohol dependence, 240, 109646
Citation
AlKhelb, Dalal; Kirunda, Andre; Ho, Thanh C; Makriyannis, Alexandros; Desai, Rajeev I. (2022). Effects of the cannabinoid CB1-receptor neutral antagonist AM4113 and antagonist/inverse agonist rimonabant on fentanyl discrimination in male rats.. Drug and alcohol dependence, 240, 109646. https://doi.org/10.1016/j.drugalcdep.2022.109646
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